EP0627082B2 - Prüfung vor der geburt für abnormitäten der chromosomen - Google Patents
Prüfung vor der geburt für abnormitäten der chromosomen Download PDFInfo
- Publication number
- EP0627082B2 EP0627082B2 EP94901864A EP94901864A EP0627082B2 EP 0627082 B2 EP0627082 B2 EP 0627082B2 EP 94901864 A EP94901864 A EP 94901864A EP 94901864 A EP94901864 A EP 94901864A EP 0627082 B2 EP0627082 B2 EP 0627082B2
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- EP
- European Patent Office
- Prior art keywords
- syndrome
- age
- risk
- pregnancies
- pregnant woman
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/743—Steroid hormones
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
- G01N33/76—Human chorionic gonadotropin including luteinising hormone, follicle stimulating hormone, thyroid stimulating hormone or their receptors
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- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
- G16H10/40—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for data related to laboratory analysis, e.g. patient specimen analysis
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/36—Gynecology or obstetrics
- G01N2800/368—Pregnancy complicated by disease or abnormalities of pregnancy, e.g. preeclampsia, preterm labour
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/38—Pediatrics
- G01N2800/385—Congenital anomalies
- G01N2800/387—Down syndrome; Trisomy 18; Trisomy 13
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/811—Test for named disease, body condition or organ function
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/815—Test for named compound or class of compounds
- Y10S436/817—Steroids or hormones
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S436/00—Chemistry: analytical and immunological testing
- Y10S436/815—Test for named compound or class of compounds
- Y10S436/817—Steroids or hormones
- Y10S436/818—Human chorionic gonadotropin
Definitions
- This invention relates to a method for antenatal screening for chromosomal abnormalities and in particular to a method for antenatal screening for Down's Syndrome.
- Maternal serum markers for Down's Syndrome are widely used for antenatal screening for this chromosomal abnormality,the most common of these markers being alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG) - either the intact molecule thereof or its beta subunit - and unconjugated estriol (uE). Disclosures relating to the use of these markers in antenatal screening for Down's Syndrome include US Patent 4,874,693, WO 89/00696 and WO 90/08325. US Patent 5,100,806 discloses the use of the beta subunit of hCG as a marker in antenatal screening for Edwards Syndrome.
- AFP alpha-fetoprotein
- hCG human chorionic gonadotropin
- Maternal serum screening is based on selecting a subgroup of women who are at the greatest risk of giving birth to a child with an abnormality, in whom the risks of an invasive diagnostic procedure are considered to be outweighed by the risk of the abnormality.
- the risk is calculated by multiplying the a priori age related risk by the likelihood ratio.
- the likelihood ratio is calculated from the relative heights of the multivariate Gaussian distribution functions of marker analytes in affected and unaffected pregnancies, corresponding to the value of the individual serum marker concentrations.
- the analyte concentrations must be corrected. Correction is performed by dividing the concentration of the analyte by the median concentration expected for that particular gestational age in women with unaffected pregnancies. This is termed the multiple of the median (MoM).
- markers AFP, hCG and uE can be used together.
- the combination of marker analytes gives significantly more information than is given by any single marker alone, or by the group of markers when used sequentially.
- the use of likelihood ratios derived from a multivariate combination is an efficient means of deriving information relating to a woman's risk of carrying an affected child.
- maternal serum screening in the first trimester of pregnancy offers considerable advantages over screening in the second trimester.
- the bonding between the mother and the foetus is less strong than in the second trimester and hence there is less psychological impact should the foetus be affected.
- the methods of pregnancy interuption are much less traumatic and are safer to the mother in the first trimester than are those available in the second trimester, particularly the late second trimester, that is approximately 18 to 25 or 26 weeks. It is in the late second trimester that several of the present methods for antenatal screening need to be performed.
- the method of the invention can be used for antenatal screening for a wide range of chromosomal abnormalities. The most significant and frequently occurring of these is Down's Syndrome (Trisomy 21). Other abnormalities which may be screened for using the invention include Edwards Syndrome (Trisomy 18), Pateaus Syndrome (Trisomy 13), Turner Syndrome, Monosomy X and Klinefelter's Syndrome. The method of the invention may be used to screen for individual abnormalities or to screen for groups of abnormalities together, for example it could be used to screen for both Down's Syndrome and Edwards Syndrome.
- Measurements are carried out using the method of the invention on blood samples taken during the first trimester of pregnancy, i.e. up to the end of the thirteenth completed week of gestation.
- the measurements are made on blood samples taken in the period between the beginning of the eighth week and the end of the thirteenth week of gestation (8th to 13th weeks).
- the woman's measured serum value for the individual serum marker is divided by the expected median value found in women with unaffected pregnancies at the same gestational age, to derive the (MoM).
- the probability that the (MoM) values for the combination of serum markers tested belongs to the multivariate distribution of values found in unaffected pregnancies is calculated.
- the same calculation is performed by reference to the probability that the individual combination of values forms part of the multivariate distribution found in abnormal pregnancies.
- the ratio of the two probabilities is termed the likelihood ratio (LR) which indicates the likelihood that an individual woman has an affected pregnancy or not.
- LR likelihood ratio
- the degree of separation between the multivariate distributions for affected and unaffected pregnancies changes with gestational age, i. e. there is a continuous change in the manner of calculating probability depending upon the gestational age. This continuous change can be built into the algorithm used in the calculation.
- An individual woman has an a priori age related risk which is independent of the maternal serum marker concentrations.
- the woman's age related risk by Baye's theorum, is modified by multiplying by the likelihood ratio (LR) obtained previously to derive a combined risk.
- LR likelihood ratio
- the concentration of the free beta subunit of hCG is higher in women with a Down's Syndrome foetus and lower in women carrying a foetus with Edwards Syndrome (Trisomy 18): Conversely the levels of PAPPA are lower than normal in women carrying children with either Down's Syndrome or Trisomy 18 during the first trimester of pregnancy. This makes it very suitable to combine measurements of PAPPA and free beta hCG in to a bivariate distribution for both affected and unaffected pregnancies in order to calculate the risk of a woman carrying an affected child in the first trimester.
- the ratio of an individual woman's assay result to the expected value for the gestational age (estimated to the day) is termed the multiple of the median (MoM) and it is this value which is required for calculation of her risk.
- f x , y 1 2 ⁇ ⁇ x ⁇ y 1 ⁇ ⁇ 2 e ⁇ 1 2 1 1 ⁇ ⁇ 2 x ⁇ ⁇ x ⁇ x 2 + y ⁇ ⁇ y ⁇ y 2 ⁇ 2 ⁇ x ⁇ ⁇ x ⁇ x y ⁇ ⁇ y ⁇ y
- Table 2 The risk factors for a 35 year old woman with various levels of free beta hCG and PAPPA are shown in Table 2. This is divided into two sections (respectively 2a and 2b) showing likelihood ratios and final risks.
- Table 2 Section 2a Likelihood ratios Free beta hCG MoM Not Assayed PAPPA MoM 0.5 1.0 2.0 Not Assayed - 0.651 2.074 6.611 0.5 9.558 16.268 103.712 661.170 1.0 2.313 1.830 11.664 74.359 2.0 0.560 0.206 1.312 8.363 Section 2b - Final risk (Likelihood ratio x age risk) Free beta HCG MoM Not Assayed PAPPA MoM 0.5 1.0 2.0 Not Assayed - 1:250 1:796 1:2536 0.5 1:3670 1:6247 1:39825 1:253889 1.0 1:888 1:703 1:4479 1:28554 2.0 1:215 1:79 1:504 1:3211
- ROC curve is shown in Figure 3 which shows the relationship between screen positive rate and detection rate using as markers free beta hCG alone + age (curve 5), PAPPA alone + age (curve 6) and a combination of these two markers + age (curve 7). From Figure 3 it can be seen that when the combination of markers is used the detection rate is increased considerably over that using either marker individually.
- Table 3 shows the actual detection rates at various screen positive rates for different combinations of serum markers. TABLE 3 MARKERS USED SCREEN POSITIVE RATE DETECTION RATE Maternal Age 5.0% 29.8% Free B hCG + Maternal Age 5.0% 49.6% PAPPA+ Maternal Age 5.0% 45.8% Free B hCG + PAPPA + Maternal Age 5.0% 77.3%
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Immunology (AREA)
- General Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- Endocrinology (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Microbiology (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Medical Informatics (AREA)
- Primary Health Care (AREA)
- Public Health (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Saccharide Compounds (AREA)
Claims (3)
- Verfahren zur vorgeburtlichen Prüfung auf eine chromosomale Abnormität in einem Fötus, umfassend:(A) Berechnen eines altersbezogenen a-priori-Risikos einer schwangeren Frau, einen Fötus zu tragen, der die chromosomale Abnormität hat,(B) bis zum Ende der dreizehnten (13.) abgeschlossenen Schwangerschaftswoche, Vermessen des Blutes der schwangeren Frau im Hinblick auf eine Konzentration von freiem beta-hCG, seinen Vorläufern und Metaboliten,(C) bis zum Ende Ende der dreizehnten (13.) abgeschlossenen Schwangerschaftswoche, Vermessen des Blutes der schwangeren Frau im Hinblick auf eine Konzentration von Schwangerschafts-assoziiertem Plasma-Protein A (PAPPA), seinen Vorläufern und Metaboliten,(D) Berechnen eines normalisierten Wertes für jede der Konzentrationen aus den Schritten (B) und (C) durch Dividieren der Konzentrationen durch einen Median-Wert, der in einer Population von Frauen mit nicht-betroffenen Schwangerschaften und demselben Gestationsalter wie die schwangere Frau gefunden worden ist,(E) Berechnen einer ersten Wahrscheinlichkeit, daß die normalisierten Werte Teil einer bivarianten Gaußschen Werteverteilung sind, die in Schwangerschaften mit der chromosomalen Abnormität gefunden wird,(F) Berechnen einer zweiten Wahrscheinlichkeit, daß die normalisierten Werte Teil einer bivarianten Gaußschen Werteverteilung sind, die in nicht-betroffenen Schwangerschaften gefunden wird,(G) Berechnen eines Likelihood-Quotienten, wobei der Likelihood-Quotient das Verhältnis von der ersten Wahrscheinlichkeit und der zweiten Wahrscheinlichkeit ist;(H) Modifizieren des altersbezogenen a-Priori-Risikos mit dem Likelihood-Quotienten.
- Verfahren nach Anspruch 1, wobei die chromosomale Abnormität Down-Syndrom ist.
- Verfahren nach Anspruch 1 oder 2, wobei die chromosomale Abnormität ausgewählt ist aus der Gruppe, bestehend aus Edwards-Syndrom, Pateaus-Syndrom, Turner-Syndrom, Monosomie X und Klinefelter-Syndrom und jegliche Kombination davon.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB929224965A GB9224965D0 (en) | 1992-11-28 | 1992-11-28 | Antenatal screening for chromosomal abnormalities |
GB9224965 | 1992-11-28 | ||
PCT/EP1993/003296 WO1994012884A1 (en) | 1992-11-28 | 1993-11-24 | Antenatal screening for chromosomal abnormalities |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0627082A1 EP0627082A1 (de) | 1994-12-07 |
EP0627082B1 EP0627082B1 (de) | 2000-03-22 |
EP0627082B2 true EP0627082B2 (de) | 2006-11-08 |
Family
ID=10725835
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP94901864A Expired - Lifetime EP0627082B2 (de) | 1992-11-28 | 1993-11-24 | Prüfung vor der geburt für abnormitäten der chromosomen |
Country Status (9)
Country | Link |
---|---|
US (1) | US6010912A (de) |
EP (1) | EP0627082B2 (de) |
JP (2) | JPH07503549A (de) |
AT (1) | ATE191089T1 (de) |
DE (1) | DE69328169T3 (de) |
DK (1) | DK0627082T4 (de) |
GB (1) | GB9224965D0 (de) |
SG (1) | SG55054A1 (de) |
WO (1) | WO1994012884A1 (de) |
Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9315230D0 (en) * | 1993-07-22 | 1993-09-08 | Kodak Ltd | Antenatal screening for chromosomal abnormalities |
US5583612A (en) * | 1994-07-14 | 1996-12-10 | Xerox Corporation | Flexible latch with relaxed engagement |
GB9410345D0 (en) * | 1994-05-24 | 1994-07-13 | Univ Oxford Brookes | Method of genetic testing |
GB9416415D0 (en) * | 1994-08-13 | 1994-10-05 | Kodak Ltd | Antenatel screening for pregnacy abnormalities |
GB9606261D0 (en) * | 1996-03-25 | 1996-05-29 | Johnson & Johnson Clin Diag | Prenatal screening for fetal abnormalities |
PT1076824E (pt) | 1998-04-29 | 2006-10-31 | Wald Nicholas John | Avaliacao pre-natal do sindroma de down |
AU2002224414B2 (en) * | 2000-10-18 | 2006-10-19 | Clarity Technologies Incorporated | Method and device for diluting a fluid and detecting analytes within a diluted fluid |
US20030204419A1 (en) * | 2002-04-30 | 2003-10-30 | Wilkes Gordon J. | Automated messaging center system and method for use with a healthcare system |
US20030201697A1 (en) * | 2002-04-30 | 2003-10-30 | Richardson William R. | Storage device for health care facility |
US20050131738A1 (en) * | 2002-05-15 | 2005-06-16 | Morris Tommy J. | System and method for handling medical information |
CA2486089C (en) | 2002-05-15 | 2013-12-17 | Tommy J. Morris | System and method for handling medical information |
US20030225596A1 (en) * | 2002-05-31 | 2003-12-04 | Richardson Bill R. | Biometric security for access to a storage device for a healthcare facility |
SE0203591D0 (sv) * | 2002-12-04 | 2002-12-04 | Siemens Elema Ab | Förfarande för beredning av ett mediakament och en medicinsk anordning |
US7725175B2 (en) | 2002-12-04 | 2010-05-25 | Kinetic Muscles, Inc. | System and method for neuromuscular reeducation |
US7315787B2 (en) * | 2003-10-07 | 2008-01-01 | Ntd Laboratories, Inc. | Multi-marker screening protocol for fetal abnormalities |
WO2009105545A1 (en) * | 2008-02-20 | 2009-08-27 | Numira Biosciences, Inc. | Methods for screening for agents that affect development |
US8105843B2 (en) * | 2009-11-04 | 2012-01-31 | Buchanan Thomas M | Methods and devices to enhance sensitivity and evaluate sample adequacy and reagent reactivity in rapid lateral flow immunoassays |
US8876714B2 (en) * | 2010-02-22 | 2014-11-04 | Wallac Oy | Systems and methods for assessing risk of chromosomal disorders |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ219609A (en) * | 1986-03-13 | 1990-09-26 | Univ Monash | Assay methods for inhibin |
US4874693A (en) * | 1986-10-10 | 1989-10-17 | Mark Bogart | Method for assessing placental dysfunction |
ATE91182T1 (de) * | 1987-07-09 | 1993-07-15 | 3I Res Expl Ltd | Praenatales screening fuer downs-syndrom. |
AU2894889A (en) * | 1988-02-01 | 1989-08-03 | Monoclonetics International Incorporated | Genetic markers for down's syndrome, fetal abnormalities and twins |
US5252489A (en) * | 1989-01-17 | 1993-10-12 | Macri James N | Down syndrome screening method utilizing dried blood samples |
US5258907A (en) * | 1989-01-17 | 1993-11-02 | Macri James N | Method and apparatus for detecting down syndrome by non-invasive maternal blood screening |
ATE252240T1 (de) * | 1989-01-17 | 2003-11-15 | Jn Macri Technologies Llc Inc | Einrichtung zum nachweis vom down syndrom durch nichtinvasive siebtestung des mütterlichen blutes |
US5100806A (en) * | 1989-03-24 | 1992-03-31 | Macri James N | Method for detecting Edwards syndrome |
US5583612A (en) * | 1994-07-14 | 1996-12-10 | Xerox Corporation | Flexible latch with relaxed engagement |
-
1992
- 1992-11-28 GB GB929224965A patent/GB9224965D0/en active Pending
-
1993
- 1993-11-24 DK DK94901864T patent/DK0627082T4/da active
- 1993-11-24 SG SG1996003810A patent/SG55054A1/en unknown
- 1993-11-24 AT AT94901864T patent/ATE191089T1/de active
- 1993-11-24 DE DE69328169T patent/DE69328169T3/de not_active Expired - Lifetime
- 1993-11-24 WO PCT/EP1993/003296 patent/WO1994012884A1/en active IP Right Grant
- 1993-11-24 JP JP6512756A patent/JPH07503549A/ja active Pending
- 1993-11-24 EP EP94901864A patent/EP0627082B2/de not_active Expired - Lifetime
-
1995
- 1995-12-04 US US08/566,467 patent/US6010912A/en not_active Expired - Lifetime
-
2004
- 2004-08-19 JP JP2004239358A patent/JP2005017305A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
ATE191089T1 (de) | 2000-04-15 |
EP0627082B1 (de) | 2000-03-22 |
US6010912A (en) | 2000-01-04 |
JPH07503549A (ja) | 1995-04-13 |
WO1994012884A1 (en) | 1994-06-09 |
EP0627082A1 (de) | 1994-12-07 |
GB9224965D0 (en) | 1993-01-20 |
DK0627082T4 (da) | 2007-03-19 |
DK0627082T3 (da) | 2000-07-03 |
DE69328169T2 (de) | 2000-07-20 |
SG55054A1 (en) | 1998-12-21 |
JP2005017305A (ja) | 2005-01-20 |
DE69328169D1 (de) | 2000-04-27 |
DE69328169T3 (de) | 2007-07-05 |
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Legal Events
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
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17P | Request for examination filed |
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